Method of preparing 2-acetamino-1-acetoxy-3-oxo-3-phenylpropane



United States Patent METHOD OF PREPARING 2-ACETAMINO-1-ACETOXY-3-OXO-3-PHENYLPROPANE Gino Carrara, Milan, Ifaly, assignor toLepetit S. A.,

Milan, Italy N 0 Drawing. Application June 29, 1950, Serial No. 171,251

The present invention relates to the preparation of intermediatessuitable for use in the manufacture ,of racemic and levo-rotatorychloramphenicol.

More particularly, the invention relates to the preparation of1-acetoxy-2-acetylamino-3-oxo-3-phenyl propane and of1-acetoxy-2-acetylamino-3-phenyl-1,3-propanediol froml-aectoxy-3-oxo-3-phenyl propane.

Various method of preparing racemic and levo-rotatory chloramphenicolare described in the literature (JACS, July 1949), in issued patents andin certain of my earlier patent applications.

I have now found that racemic and levo-rotatory chloramphenicol can beprepared in simple and convenient manner by starting with, for example,1-acetoxy-3-oxo-3- phenyl propane. In accordance with the presentinvention, this starting compound is nitrosated with sodium nitrite inan acetic solution or with an alkyl nitrite in an ethereal solution inthe presence of HCl. The isonitroso derivative is subjected, evenwithout isolating it, to a selective reduction and acylated, or it issubjected to a reducing acylation in order to obtainl-acetoxy-2-acetamino-3- oxo-3-phenyl-propane.

For the production of chloramphenicol, the 1-acetoxy-2-acetamino-3-oxo-phenyl propane is reduced in the presence of catalystsand a mixture of l-acetyl-2-acetamino-3- phenyl-l,3-propandiol of threoand erythro form is obtained. Without separating the two products, thismixture is dissolved in concentrated sulphuric acid and thecorresponding acetoxy-oxazolidine in a sulphuric acid solution isobtained in accordance with my patent application Ser. No. 132,985,filed Dec. 14, 1949. Without it being necessary to isolate it, thelatter is subjected to nitration with concentrated nitric acid and fromthe nitrating mixture a solution of the hydrochloride ofl-p-nitrophenyl-Z-amino-1,3-propandiol of threo form is finallyobtained. From this hydrochloride the base may be isolated and separatedinto the optical antipodes according to my co-pending application Ser.No. 132,986, filed Dec. 14, 1949, now abandoned. The solution of thehydrochloride of the above mentioned racemate, or the solution of thehydrochloride of the levo-rotatory base separated as above may beconverted to racemic chloramphenicol or levo-rotatory chloramphenicol bysubstitution of hydrogen in the amino group by thedichloracetic residueby a reaction according to Schotten Baumann.

The reactions involved in the process claimed herein may be graphicallyrepresented as follows:

O0 041111011200 OCH:

O0 o-g-omooocm NOE QeH-cn-cmoooom 2,695,309 Patented Nov. 23, 1954nitrite. On completion of the reaction 1.450 kgs. ice and 1.160 kgs.acetic anhydride are added. While etficiently stirring further 1.450kgs. ice, 0.580 kg. acetic anhydride iand 1 kg. zinc are added, keepingthe temperature be- On completion of the reaction the mixture isfiltered.

The uppers on the filtre are repeatedly dissolved with acetone and theacetonic extracts are concentrated to a paste. The filtrate is likewiseconcentrated in vacuum to a paste. The two residues are broughttogether, the mixture is repeatedly diluted with water and the waterinsoluble portion is recrystallized from alcohol. Thelacetoxy-2-acetamino-3-oxo-3-phenyl-propane is obtained, of which themelting point is 84 -85 C.

The above mentioned product is dissolved in 10 parts methylic alcohol, 2parts palladium-carbon catalyst with 5% palladium are added andreduction at ordinary pressure and temperature is carried out tillabsorption of 10% excess over the theoretical value of hydrogen. Theproduct is filtered from the catalyst and methylic alcohol is distilledin vacuum. The residue obtained, which is a mixture ofl-acetoxy-Z-acetamino 3 phenyl-1,3-propandiol of threo and erythro form,is dissolved in accordance with my application 132,985 in 3 times itsweight concentrated sulphuric acid, and the solution is allowed to restat room temperature during 12 hours.

This solution is poured at a temperature of about 15 C. into three partsconcentrated nitric acid of a density of 1.42. It is allowed to restduring about one hour at this temperature and during about half-an'hourat +15 C. It is then poured on ice. It is thoroughly extracted by ethylacetate after having neutralised it by means of sodium carbonate. It isdried and the acetic extract is distilled. The residue is dissolved in10 parts 5% hydrochloric acid and heated in a water bath during twohours. It is then concentrated in vacuum to a small volume and admixedwith an equal part of concentrated hydrochloric acid, and thehydrochloride of 1-nitrophenyl-2-amino-l,3- propandiol is allowed tocrystallize. Its melting point is 177180 C.

From this hydrochloride the base may be insulated and separated into thetwo antipodes in accordance with my patent application Ser. No. 132,986.

The hydrochloride of the racemic nitrobase or the hydrochloride of thelevo-rotatory nitrobase are suspended in water and treated whileactively stirring with a slight excess of sodium bicarbonate and withthe stoichiometric quantity of the chloride of the dichloracetic acid.

From the reaction the racemic chloroamphenicol or the levo-rotatorychloroamphenicol mixed with an organic salts are separated.

The separated products are filtered and recrystallized from water andare therefore obtained in a condition of sufficient chemical purity.

[oz] 22.5 (2% in ethyl acetate) Racemic chloramphenicol, white crystals,melting point What I claim is:

1. Process for the preparation of an intermediate suitable for themanufacture of antibiotically active chloramphenicol, which comprisesreacting 1-acetoxy-3-oxo-3- phenylpropane with a member of the groupconsisting of sodium and alkyl nitrites under acid conditions at atemperatnre not higher than about 35 0., adding tothe resulting acidicreaction mixture an acetylating agent and a metal which generates hydroen in acid solution, and keeping the temperature below 20 to effectreduction and acetylation of the formed 2-isonitroso group to produce1-acetoxy-2-acetainino-3-oxo-3-nhenylpropane.

2; Process for the preparation of an intermedia e suitable f r the mnufacture of antibi ticallv active chloramphenicol, which com risesreacting 1-acetoxv-3-oxo-3 phenylpropane with sodium nitrite in aceticacid so ution at a. temperature of about 3035 C., adding to theresulting acidic reaction mixture an acetylating agent and a metal whichgenerates hydrogen in acetic acid solution, and keeping the temperaturebelow 20 C. to etfect reduction and acetylation of the formed2-isonitroso group to produce1-acetoxy-2-acetamino-3-oxo-3-phenylpropanm 3. Process for thepreparation of an intermediate suitable for the manufacture ofantibiotically active chloramphenicol, which comprises reacting1-acetoxy-3-oxo 3- phenylpropane with sodium nitrite inacetic acidsolution at. a temperature of about 30/ 35 C., adding to the resultingacidic reaction mixture acetic anhydride and zinc, and keeping thetemperature below 20 C. to etfect reduction and acetylation of theformed 2-nitroso group to produce1-acetoxy-2-acetamino-3-oxo-3phenylpropane.

References Cited in the file. of, this patent UNITED STATES PATENTSNumber Name Date.

1,877,795 Bockmuhl et al. Sept. 2,0, 1932- 1,948,162 Bockmuhl et al Feb.20, 1934 1,995,709 Hartung May 26, 1935 1,995,710 Hartung May 26, 19352,306,765 Stiller Dec. 29, 1942 2,359,707 Baltzly et a1. Oct. 3, 19442,483,884 Crooks et a1. Oct. 4, 1949 2,483,885 Crooks et a1. Oct. 4,1949 Number Name Date 2,514,377 Crooks et-al July 1-1, 1950 2,521,809Tishler et a1. Sept. 12, 1950 2,521,810 Tishler et a1. Sept. 12, 1950FOREIGN PATENTS Number Country Date 63,224 Norway Feb. 17, 1941 842,117France Feb. 27, 1939 OTHER REFERENCES Countroulis et al., J. Am. Chem.Soc," vol. 71, July 1949, pp. 246310 2468.

Long et al., J. Am. Chem. Soc., vol., 71, July 1949, pp. 2468-72.

Darmon, Comptes Rendus Acad. Sci., vol. 197 (1933), page 1329.

Albertson et al., J. Am. Chem. Soc., vol. 70 (1948),

1. PROCESS FOR THE PREPARATION OF AN INTERMEDIATE SUITABLE FOR THEMANUFACTURE OF ANTIBIOTICALLY ACTIVE CHLORAMPHENICOL, WHICH COMPRISESREACTING 1-ACETOXY-3-OXO-3PHENYLPHROPANE WITH A MEMBER OF THE GROUPCONSISTING OF SODIUM AND ALKYL NITRITES UNDER ACID CONDITIONS AT ATEMPERATURE NOT HIGHER THAN ABOUT 35* C., ADDING TO THE RESULTING ACIDICREACTION MIXTURE AN ACETYLATING AGENT AND A METAL WHICH GENERATESHYDROGEN IN ACID SOLUTION, AND KEEPING THE TEMPERATURE BELOW 20* TOEFFECT REDUCTION AND ACETYLATION OF THE FORMED 2-ISONITROSO GROUP TOPRODUCE 1-ACETOXY-2-ACETAMINO-3-OXO-3-PHENYLPROPANE.